Tag Archives: Medicine

Cooling reduces death and disability in newborns deprived of oxygen at birth

Therapeutic hypothermia reduces risk of death and disability in infants with hypoxic-ischaemic encephalopathy, according to a new study by David Edwards and colleagues published in the British Medical Journal.

Hypoxic-ischaemic encephalopathy (damage to cells in the brain and spinal cord because of lack of oxygen) is a major cause of death and disability worldwide but there currently is no specific treatment available for it. Therapeutic hypothermia (cooling the body below the normal temperature of 37oC) has been reviewed previously and tested in several clinical trials for newborns with hypoxic-ischemic encephalopathy but the results have so far been inconclusive and consensus in the medical profession has not been reached.

Edwards and colleagues carried out a meta-analysis which took advantage of new studies, including results from the TOBY trial, and recently available additional data from previously reported studies to determine whether moderate hypothermia after hypoxic-ischemia encephalopathy in newborns improves survival and neurological outcome 18 months later.

The researchers analysed data from 1320 infants in 10 different randomised controlled trials (studies which reported at least mortality data). They also assessed data from a subset of three trials which had similar entry requirements—evidence of oxygen deprivation of birth and moderate and severe encephalopathy— which investigated neurological outcomes up to 18 months of age in 767 infants.

The investigators found that therapeutic hypothermia significantly reduced the combined death and severe disability rates in the subset of three trials with outcome data at 18 months. Cooling newborns deprived of oxygen at birth not only increased survival with normal neurological function but also reduced the rates of severe disability, cerebral palsy, severe neuromotor delay, severe neurodevelopmental delay and blindness. They observed no association between the severity of encephalopathy and the effect of cooling treatment. In their analysis of all the 10 different trials, the researchers showed that hypothermia therapy significantly reduced mortality.

“In the absence of any specific intervention to improve the dismal prognosis of infants with hypoxic-ischaemic encephalopathy, clinical enthusiasm for a novel treatment is understandable,” write the investigators, “this new meta-analysis … provides the highest level evidence that moderate hypothermia is efficacious in infants with hypoxic-ischaemic encephalopathy”. More work is needed to follow up the infants enrolled in these therapeutic hypothermia studies to determine whether they continue to reap the benefits of cooling therapy in later childhood.

ResearchBlogging.orgEdwards, A., Brocklehurst, P., Gunn, A., Halliday, H., Juszczak, E., Levene, M., Strohm, B., Thoresen, M., Whitelaw, A., & Azzopardi, D. (2010). Neurological outcomes at 18 months of age after moderate hypothermia for perinatal hypoxic ischaemic encephalopathy: synthesis and meta-analysis of trial data BMJ, 340 (feb09 3) DOI: 10.1136/bmj.c363

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Synovial fibroblasts spread Rheumatoid Arthritis to other joints

New research shows that rheumatoid arthritis synovial fibroblasts help spread destructive arthritis to other joints in the body, according to research by Lefevre and colleagues published online on the 8th November in the journal Nature Immunology.

Rheumatoid arthritis (RA) is a chronic, systemic inflammatory disease that can affect many tissues and organs, but mainly causes inflammation in the lining of the joints. RA is an autoimmune disease and is caused by abnormal immune responses whereby the body’s own immune system attacks itself. About 1% of the population in developed countries suffer from RA, and it leads to progressive joint destruction resulting in chronic pain, loss of mobility and loss of function of the joint. One of the key features of RA is it usually starts in one or two joints and then spreads to most joints in the body. The researchers wanted to understand what host factors are involved in the spread of disease. They were particularly interested in special cells called rheumatoid arthritis synovial fibroblasts (RASFs), which are present in high numbers in rheumatoid synovium (lining of the joint) and had previously been shown to contribute to the progression of RA by attaching to, invading and degrading cartilage and bone.

The researchers used a SCID mouse model of RA. SCID mice have a severe immunodeficiency and cannot mount a humoral or cellular immune response therefore you can graft tissues from another species (in this case human cartilage and RASFs or rheumatoid synovium) subcutaneously (under the skin) and it will not reject it. This means the researchers could study the biology of RA and how it spreads over a long period of time. Using this in vivo model they showed not only that human RASFs attached to, invaded and degraded co-implanted cartilage but also could spread through the mouse body to another cartilage implant on the other side of the mouse (contralateral implant). Experiments that inject RASFs 2 weeks after surgical cartilage implantation suggests that RASF migration was due to neovasculisation (formation of micro blood vessels) of the cartilage and not due to the surgery itself or wound healing. The researchers then implanted rheumatoid synovium as a natural source of RASFs. These “natural” RASFs also migrated to, invaded and degraded the RASF-free cartilage contralateral implant. The organs of 20 mice used in the implant experiments were examined to determine the route of RASF migration; the majority of human RASFs were found in the spleen but no RASFs were detected in the lungs, intestines, heart, liver or skin distant from the implants. Human RASFs were also found in mouse joints and ear cartilage and PCR analysis revealed that human RASFs were present in the bloodstream of experimental mice. Finally, the researchers showed that RASFs are able to transmigrate through cell monolayers, which is an important requirement for entering and leaving the bloodstream at sites of disease or to access distal sites.

This work shows that the characteristic progressive joint destruction seen in RA is in part due to RASFs, which can migrate long distances and spread the destructive arthritis from one primary joint to other joints in the body. More work is needed to understand if other cellular factors are involved in RASF migration. This could provide clues for new drug targets to prevent the spread of RA, which is hugely important since the cause of RA is unknown and there is currently no known cure.

ResearchBlogging.org
Lefèvre, S., Knedla, A., Tennie, C., Kampmann, A., Wunrau, C., Dinser, R., Korb, A., Schnäker, E., Tarner, I., Robbins, P., Evans, C., Stürz, H., Steinmeyer, J., Gay, S., Schölmerich, J., Pap, T., Müller-Ladner, U., & Neumann, E. (2009). Synovial fibroblasts spread rheumatoid arthritis to unaffected joints Nature Medicine DOI: 10.1038/nm.2050

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Pneumonia is world’s biggest childhood killer

Pneumonia is an acute respiratory infection of the lungs caused by viruses, bacteria and fungi. Despite pneumonia being treatable and preventable, estimates suggest that over 2 million children die every year from pneumonia, making it the leading cause of childhood death worldwide.

On the 2nd November the World Health Organisation and the United Nations Children’s Fund launched the Global Action Plan for Prevention and Control of Pneumonia (GAPP) to raise awareness of the devastating death toll from pneumonia and call on governments, public health policy-makers, charities, non-governmental organisations and the public to work together to implement their action plan.

The GAPP aims to:

  • protect children from pneumonia by providing an environment with low risk of pneumonia (strategies include increasing hand-washing or providing adequate nutrition)
  • prevent pneumonia in children (with vaccinations against the microorganisms that cause it such as Streptococcus pneumonia and Haemophilus influenzae b)
  • Treat children sick with pneumonia with the correct healthcare and antibiotics.

If successful their plan could save 5.3 million children from dying of pneumonia by 2015.

A new “Health in Action” article in this week’s PLoS Medicine by Enarson and colleagues describes efforts by the government in Malawi to introduce a national programme to cut childhood deaths from pneumonia. This strategy, known as standard case management (or SCM), aims to ensure that children with pneumonia in Malawi receive effective treatment, like antibiotics and oxygen therapy.

The SCM strategy for treatment of children with pneumonia in Malawi was based on a similar programme established by the International Union against Tuberculosis and Lung Disease. This was a cost-effective health intervention that has been successfully used to prevent and control tuberculosis in 190 countries. To improve the management of severe and very severe pneumonia in children admitted to district hospitals (accessible to the whole population) the Child Lung Health Programme (CLHP) for pneumonia in Malawi focused on:

  • getting lasting commitment from the government to sustain the health programme
  • establishing diagnosis and treatment based on the SCM
  • teaching clinical staff the SCM
  • safeguarding uninterrupted supplies of standardised drugs and equipment needed for pneumonia treatment
  • recording and reporting clinical outcomes of pneumonia
  • supervising and evaluating the programme

The CLHP in Malawi has been in place since 1999 and was funded by the Malawi government and support from the Bill and Melinda Gates foundation. The CLHP was gradually scaled-up across the entire country over the next 5 years. Between Oct 2000 and Dec 2005, the CLHP successfully trained 312 health workers (including nurses and medical assistants) in SCM and there was a consistent increase in the numbers of children receiving pneumonia treatment in district and central hospitals. Furthermore, the proportion of children dying from pneumonia dropped from 18.6% to 8.4%. The CLHP is now successfully maintained by the Malawi government after the end of external funding for the project. However, there are still ongoing challenges that need to be addressed, such as a shortage of healthcare workers and the effects of malnutrition, malaria, HIV/AIDS and anaemia on the outcome of pneumonia infection.

The reduction of child mortality by two-thirds by 2015 is a major challenge set by the United Nations Millenium Development goals and programmes, like the CLHP in Malawi to reduce deaths from pneumonia, will make a significant contribution to this goal.

Enarson, P., Gie, R., Enarson, D., & Mwansambo, C. (2009). Development and Implementation of a National Programme for the Management of Severe and Very Severe Pneumonia in Children in Malawi PLoS Medicine, 6 (11) DOI: 10.1371/journal.pmed.1000137
ResearchBlogging.org

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HIV vaccine trial not so positive after all

In September, scientists from the Thailand Ministry of Public Health, in collaboration with the U.S Army, hailed a breakthrough in research towards a HIV vaccine….a positive result. Now, the full results by Rerks-Ngarm and colleagues, published on 20th October in the New England Journal of Medicine, reveal that the outcome of the trial was not so positive after all…..in fact it was statistically insignificant (i.e. the results could have happened by chance).

 

Lab work 2The $105 million RV144 HIV/AIDS vaccine clinical trial included more than 16,400 volunteers aged 18 – 30 yrs old. Half were randomly picked to receive a combination of two HIV vaccines (ALVAC and AIDSVAX) whilst the rest received a placebo vaccine. The volunteers were monitored after a 6 month vaccination programme and every 6 months for a further 3 years. On the 24th September, the world media reported that the ALVAC-AIDSVAX combo was the first experimental vaccine to have a statistically significant effectiveness (~31%) at reducing the risk of HIV infection.

 

However, following the publication of the full analysis of the results last week the response from the scientific world has been somewhat muted. The scientists from the study themselves state that the results show only a “modest benefit” and reveal a 26% effectiveness at reducing the risk of HIV infection which was statistically insignificant (could have happened by chance). Also, the protective effects of the vaccine reduced after 12 months and the vaccine did not protect those at high risk of HIV infection (intravenous drug users and sex workers)

 

So how come there are two very different results within the same study? Basically, it is all down to which volunteers you include in the analysis of the results. The study started with 16,402 people who were randomly assigned to receive the vaccine or the placebo over the course of six months. However, 7 people were found to be already HIV-positive at the beginning and so were removed from the results. This meant that 8197 people received the HIV vaccine whilst 8198 received the placebo (16,395 total). During the course of the study, 2021 people were excluded from the results from the vaccine arm of the study and 1832 people were excluded from the results from placebo arm of the study. People were excluded for a number of reasons such as they were not given the full 6 doses of the vaccine during the course of the study, they were given the wrong dose of vaccine or were not given the vaccine in the correct time period. This meant that the final number of people that match all the experimental criteria for the study analysis was 6176 in the vaccine group and 6366 people in the placebo group (12,542 total).

 

The level of success of the vaccine depends on which set of people you pick to analyse:

  • the “modified intention to treat” set are the 16,395 people at the beginning of the trial (discounting the 7 people who were HIV-positive). Analysis of their results gives you the statistically significant 31% effectiveness of the vaccine
  • the “per protocol” set are the 12, 542 people at the end of the study who have received the correct dose and number of vaccines, and were HIV-negative during the course of the vaccination programme. Analysis of their results gives you the statistically insignificant 26% effectiveness of the vaccine.

 

The full results demonstrate just how difficult it is to interpret results from large clinical trials and the complexities in using statistical significance for confirming evidence-based research. The full analysis of the people who received the correct number of vaccines and the correct dose during the correct time period suggests that the ALVAC-AIDSVAX vaccine trial was not successful and more work is needed to find that elusive protective HIV vaccine.

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And the winner is…………….

So it’s award season in the scientific world………and it’s a biggie….The Nobel Prize. Every year since 1901 the Nobel Prize has been awarded for physics, chemistry, physiology or medicine, literature and for peace, and from 1968 the Sveriges Riksbank Prize for Economic Sciences was also introduced. Winners take home a medal, a diploma and a big fat cheque for 10m Swedish Kronor (~£800,000)…oh and the small bonus of international recognition for your life’s hard work.

So this year the science gongs go to:

In layman’s terms that is;

  • Physiology of Medicine; understanding how the ends of DNA molecules are maintained (“just like the plastic tips on shoelaces”) which has important implications for cancer and ageing.
  • Physics; revolutionising modern communications by transmitting light along glass fibres over huge distances (it’s how we get our broadband) and the CCD is the eye of digital cameras (it’s in the camera in our mobile phones).
  • Chemistry; understanding the mechanism of how cells make proteins, which is absolutely fundamental to life.

Now, let’s not forget the other important prize of the year…..The Ig Nobel’s (the website alone is worth a look for the picture of Nobel Laureates wearing one of this year’s inventions, a bra/facemask, and a video about the first recorded case of a homosexual necrophiliac duck….yes really).

2009 Ig Nobel Prize Ceremony. Left to right; Wolfgang Ketterle, Elena Bodnar, Orhan Pamuk and Paul Krugman. Photo; Alexey Eliseev

2009 Ig Nobel Prize Ceremony. Left to right; Wolfgang Ketterle, Elena Bodnar, Orhan Pamuk and Paul Krugman. Photo; Alexey Eliseev

The “Igs” are awarded to scientists whose work “first makes people laugh, and then makes people think”. This year’s highlights include prizes for:

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